Ostepontin is one of the major noncollagenous bone matrix proteins produced by osteoblasts and osteoclasts. Substrate-bound osteopontin promotes attachment of osteoclasts, whereas soluble osteopontin can alter calcium levels in osteoclasts, suppress inducible nitric oxide synthase induction in kidney cells and macrophages and serve as a chemoattractant.
Increased production of osteopontin has been associated with osteoporosis and autoimmune diseases, including systemic lupus erythematosis and multiple sclerosis.
Multiple sclerosis (MS) affects approximately one million people worldwide with women twice as likely to have the disease. At present, multiple sclerosis is uncurable and the cause is unknown. In multiple sclerosis, inflammation of nerve tissue destroys the myelin covering of nerve cells axons, leaving areas of scar tissue. This patchy loss of myelin in the brain and spinal cord slows communication between nerve cells, leading to symptoms such as muscle spasms, weakness, sensory deficits and visual disturbances. Chabas et al., Science 294: 1731-1735 (2001) studied the influence of osteopontin on autoimmune demyelinating disease and found that osteopontin transcripts were increased in an experimental mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, and that osteopontin-deficient mice were resistant to progressive experimental autoimmune encephalomyelitis and had frequent remissions.
Humans with systemic lupus erythematosus overexpress osteopontin.
Osteoarthritis-affected cartilage exhibits enhanced expression of fibronectin and osteopontin. Yoshitake et al. Proc. Nat'l Acad. Sci. USA 96: 8156-8160 (1999) reported that osteopontin-deficient knockout mice are resistance to ovariectomy-induced bone resorption. Post menopausal osteoporosis is one of the most common diseases affecting aged women. Withdrawal of estrogen after menopause causes loss of bone mineral because of an increase in osteoclastic bone resorption. Supplementation with estrogen can reduce bone loss not only in humans but also in animal models.
Astrogorgiadiol (1) is a naturally occurring occurring vitamin D analogue with antiproliferative properties. Astrogorgiadiol was isolated from a Japanese marine sponge of the genus Astrogorgia (Fusetani et al. (1989) Tetrahedron Letters 30(50): 7079-7082), and was found to inhibit cell division of starfish eggs. Synthesis of astrogordiadiol was reported in Taber, D. F. and Malcolm, S. C. (2001) Journal of Organic Chemistry 66: 944-954, the disclosures of which are hereby incorporated by reference.